In many instances, the suppression of biosynthesis of sterols is desirable. For example, it is often desirable to suppress the formation of cholesterol in animals, including humans, whereby the serum cholesterol level in the animal will be lowered.
The concentration of cholesterol in blood serum has been correlated with a number of diseases, particularly atherosclerosis. Atherosclerosis is a condition marked by the formation of plaques in the arterial system. Cholesterol and cholesterol esters are major components of these plaques. While the etiology of the disease is not completely known, it appears that an elevated serum cholesterol level contributes to the development and progression of atherosclerosis.
Cholesterol in animals is derived from two sources, first the intake and absorption of dietary cholesterol and second the biosynthesis of cholesterol from acetate by cells of various organs of the body, e.g., liver, intestines, and skin. The biosynthesis of cholesterol and other sterols from acetate in the body involves a complex sequence of reactions, one of which is the conversion of 3-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid. This reaction is considered to be a major regulation point in the normal biosynthesis of cholesterol in cells. A key regulatory enzyme involved at the level of the enzymatic formation of mevalonic acid is 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). Lowering the activity of HMG-CoA reductase serves to inhibit the biosynthesis of mevalonic acid in cells. If the biosynthesis of mevalonic acid can be inhibited in vivo, production of sterols is reduced, and serum cholesterol levels can thereby be lowered.
Additionally, the growth and proliferation of cells of higher organisms and certain microorganisms, such as yeast and fungi, involve the formation of sterols. Accordingly, inhibition of the biosynthesis of mevalonic acid, and thus reduction of sterol formation, is effective to inhibit the growth of cells, both normal and tumorous. Inhibition of the biosynthesis of sterols also has the effect of inhibiting the growth of certain microorganisms, thereby combatting infections.
In addition to its role in sterol biosynthesis, mevalonic acid is an important precursor of a number of other cell constituents. Thus, while bacteria are generally considered not to need or contain sterols, their growth and proliferation requires synthesis of mevalonic acid and the products derived therefrom. Accordingly, inhibition of mevalonic acid synthesis should inhibit bacterial growth.
It is known from U.S. Pat. No. 4,202,891, which is herein incorporated by reference, that certain 15-oxygenated sterols are effective in the inhibition of the biosynthesis of mevalonic acid and of sterols. A number of desirable side effects can be derived from the inhibition of the biosynthesis of mevalonic acid, including suppressing the formation of cholesterol in animals, whereby serum cholesterol levels may be lowered.
In accordance with the present invention, it has been found that 15-oxygenated sterols in which the saturated side chain has been derivatized are particularly effective to lower the activity of HMG-CoA reductase and, accordingly, to inhibit the biosynthesis of sterols. Additionally, these 15-oxygenated sterols may lower serum cholesterol levels by inhibiting cholesterol biosynthesis, blocking the absorption of cholesterol and/or other mechanisms.
There have been many attempts to derive a facile process whereby the saturated side chains of sterols may be derivatized. These processes, however, have suffered from problems such as low yields and multiple products, making them unsuitable for application to the preparation of side chain derivatized sterols. Of particular interest has been the oxidation of the saturated side chain with trifluoroperacetic acid. See, e.g., Deno and Meyer, J. Org. Chem., 44, 3383-3385, and Takano et al., Chem. Lett., 1265-1266, the disclosures of which are herein incorporated by reference.